Micafungin is a novel anti-fungal drug of pneumocandins, and it inhibits the synthesis of the main ingredient of fungi cell walls, i.e. β-1,3-D-dextran, and therefore destroy the structure of fungal cells, thus leading to cytolysis. Micafungin is widely used for treating various infections, such as infections caused by Aspergillus, Candida, Cryptococcus, Mucor, Actinomyces, Histoplasma, Dermatophytes and Fusarium and the like.
Micafungin Sodium (also named as FK463) is the active pharmaceutical ingredient of Mycamine. The chemical structure of micafungin Sodium is shown as follows:

Sodium
5-[(1S,2S)-2-[(3S,6S,9S,11R,15S,18S,20R,21R,24S,25S,26S)-3-[(R)-2-carbamoyl-1-hy droxyethyl]-11,20,21,25-tetrahydroxy-15-[(R)-1-hydroxyethyl]-26-methyl-2,5,8,14,17,23-hexaoxo-18-[4-[5-(4-pentoxyphenyl)isoxazol-3-yl]benzoylamino]-1,4,7,13,16,22-hex aazatricyclo[22.3.0.09,13]heptacosan-6-yl]-1,2-dihydroxyethyl]-2-hydroxy phenyl sulfate.
The compound of formula I is a polypeptide compound with poor stability, and its quality and efficacy will be affected by degraded products generated during transportation or long-term preservation. And it is difficult to crystallize the compound of formula I, and generally, it is amorphous.
U.S. Pat. Nos. 6,107,458 and 7,199,248 and WO 96/111210 disclosed methods for preparing and purifying the compounds of Formula I. Wherein, in U.S. Pat. No. 7,199,248, Micafungin DIPEA (diisopropylethylamine) salt was purified through filtration and chromatographic separation, and then precipitated with acetone and ethyl acetate to give the amorphous form of the compound of formula I.
In Atsushi Ohigashi et al., “Process Development of Micafungin, a Novel Lipopeptide Antifungal Agent”, Journal of Synthesit Organic Chemistry, 2006, Vol 64, 12, it was disclosed that the compound of formula I can be precipitated by adding a mixture of acetone and ethyl acetate to the elution solution of the compound of formula I from ion exchange, so as to give the amorphous compound of formula I. Before drying, the content of solvent in the precipitate of the compound of formula I was high (Dry/Wet=0.25), and about 75% of solvent is contained in the precipitate of the compound of formula I. For reducing the content of solvent below the standard, the drying time has to be extended. However, the extension of drying time will result in an increase in the degraded products of the compound of formula I and reduction in the quality.
In addition, the patent application WO 03/018615 of Fujisawa Pharmaceutical Co., Ltd. disclosed a new crystal form of the compound of the formula I and a preparation method thereof. In WO03/018615, the compound of formula I in amorphous form was dissolved in an aqueous single alcohol solution or aqueous acetone solution, and a solvent, such as ethyl acetate, methylene chloride, acetone and acetonitrile was added, so as to give needle-like crystals of the compound of formula I of B82 type. The crystal was obtained in an organic solvent, showed needle-like under microscope, and has peaks at the following 2θ angles in the X-ray diffraction pattern: 4.60, 5.4°, 9.0°, 9.8°, 16.9°.
YAMASHITA et al., from Fujisawa Pharmaceutical Co., Ltd. disclosed (“Study of Industrial Manufacturing Methods for Micafungin (FK463)”, Seibutsu kogaku Kaishi, 2005, Vol 83) that needle-like crystals of FK463 were successfully obtained through optimization of solvent and control of pH, however, no specific embodiments and crystal data were disclosed. Since the prior patent application WO03/018615 of the company disclosed B82-type needle-like crystals of the compounds of formula I, it is assumed that YAMASHITA et al. also obtained needle-like crystals of B82 type.
The present inventors prepared needle-like crystals of B82 type according to the method of Example 1 in WO03/018615, and the obtained crystal was observed under an optical microscope, which is about 1 μm in size and a fine needle-like crystal. When the crystals are subjected to subsequent steps, such as filtration, drying or the like, the present inventors found that it is difficult to filter the crystals of the compound of formula I since the crystals of B82 type are in a fine needle-like form, and the operation time is long; before drying the crystals, the content of solvent in the compound of formula I (Dry/Wet) was about 0.25, and a large amount of organic solvent are contained in the crystals. The content of solvent has to be in line with API requirements by increasing the drying temperature or drying time during the drying process. However, such drying process will increase the degraded product of the compound of formula I, seriously affecting the quality and stability of API.
At present, it is disclosed that solids of Micafungin sodium are of poor stability, and can only be stored at a low temperature or a large amount of excipients have to be added to ensure its stability, which greatly limits the development of pharmaceutical uses of Micafungin sodium. If a stable solid of Micafungin sodium can be found, it can be prepared into various different formulations, such as freeze-dried powder, tablets, capsules, ointment, etc., to facilitate the use for different patients.
Therefore, there is an urgent need in the art to obtain a stable form of the compound of formula I with better stability, thereby achieving better commercial production.